tbuckley/cabot-search huggingface dataset:
In vivo interrogation of regulatory genomes reveals extensive quasi-insufficiency in cancer evolution
Authors: Anja Fischer, Robert Lersch, Niklas de Andrade Krätzig, Alexander Strong, Mathias J Friedrich, Julia Weber, Thomas Engleitner, Rupert Öllinger, Hsi-Yu Yen, Ursula Kohlhofer, Irene Gonzalez-Menendez, David Sailer, Liz Kogan, Mari Lahnalampi, Saara Laukkanen, Thorsten Kaltenbacher, Christine Klement, Majdaddin Rezaei, Tim Ammon, Juan J Montero, Günter Schneider, Julia Mayerle, Mathias Heikenwälder, Marc Schmidt-Supprian, Leticia Quintanilla-Martinez, Katja Steiger, Pentao Liu, Juan Cadiñanos, George S Vassiliou, Dieter Saur, Olli Lohi, Merja Heinäniemi, Nathalie Conte, Allan Bradley, Lena Rad, Roland Rad
Journal: Cell Genomics (2023)

In contrast to mono- or biallelic loss of tumor-suppressor function, effects of discrete gene dysregulations, as caused by non-coding (epi)genome alterations, are poorly understood. Here, by perturbing the regulatory genome in mice, we uncover pervasive roles of subtle gene expression variation in cancer evolution. Genome-wide screens characterizing 1,450 tumors revealed that such quasi-insufficiency is extensive across entities and displays diverse context dependencies, such as distinct cell-of-origin associations in T-ALL subtypes. We compile catalogs of non-coding regions linked to quasi-insufficiency, show their enrichment with human cancer risk variants, and provide functional insights by engineering regulatory alterations in mice. As such, kilo-/megabase deletions in a Bcl11b-linked non-coding region triggered aggressive malignancies, with allele-specific tumor spectra reflecting gradual gene dysregulations through modular and cell-type-specific enhancer activities. Our study constitutes a first survey toward a systems-level understanding of quasi-insufficiency in cancer and gives multifaceted insights into tumor evolution and the tissue-specific effects of non-coding mutations.
Tissue-resident Lachnospiraceae family bacteria protect against colorectal carcinogenesis by promoting tumor immune surveillance
Authors: Xusheng Zhang, Dou Yu, Di Wu, Xintong Gao, Fei Shao, Min Zhao, Jiang Wang, Jiangwen Ma, Wenzhao Wang, Xiwen Qin, Yi Chen, Pengyan Xia, Shuo Wang
Journal: Cell Host & Microbe (2023)
Aspergillus fumigatus hijacks human p11 to redirect fungal-containing phagosomes to non-degradative pathway
Authors: Lei-Jie Jia, Muhammad Rafiq, Lukáš Radosa, Peter Hortschansky, Cristina Cunha, Zoltán Cseresnyés, Thomas Krüger, Franziska Schmidt, Thorsten Heinekamp, Maria Straßburger, Bettina Löffler, Torsten Doenst, João F. Lacerda, António Campos, Marc Thilo Figge, Agostinho Carvalho, Olaf Kniemeyer, Axel A. Brakhage
Journal: Cell Host & Microbe (2023)

The decision whether endosomes enter the degradative or recycling pathway in mammalian cells is of fundamental importance for pathogen killing, and its malfunctioning has pathological consequences. We discovered that human p11 is a critical factor for this decision. The HscA protein present on the conidial surface of the human-pathogenic fungus Aspergillus fumigatus anchors p11 on conidia-containing phagosomes (PSs), excludes the PS maturation mediator Rab7, and triggers binding of exocytosis mediators Rab11 and Sec15. This reprogramming redirects PSs to the non-degradative pathway, allowing A. fumigatus to escape cells by outgrowth and expulsion as well as transfer of conidia between cells. The clinical relevance is supported by the identification of a single nucleotide polymorphism in the non-coding region of the S100A10 (p11) gene that affects mRNA and protein expression in response to A. fumigatus and is associated with protection against invasive pulmonary aspergillosis. These findings reveal the role of p11 in mediating fungal PS evasion.
How the Taliban are destroying female doctors in Afghanistan
Authors: Sally Howard, Geetanjali Krishna
Journal: BMJ (2023)

Female doctors are disappearing following Taliban bans. That’s bad news for a country where primary healthcare is on the verge of collapse. <b>Sally</b><i></i><b>Howard</b><i></i>and<i></i><b>Geetanjali</b><b>Krishna</b> report
The molecular consequences of androgen activity in the human breast
Authors: Florian Raths, Mehran Karimzadeh, Nathan Ing, Andrew Martinez, Yoona Yang, Ying Qu, Tian-Yu Lee, Brianna Mulligan, Suzanne Devkota, Wayne T. Tilley, Theresa E. Hickey, Bo Wang, Armando E. Giuliano, Shikha Bose, Hani Goodarzi, Edward C. Ray, Xiaojiang Cui, Simon R.V. Knott
Journal: Cell Genomics (2023)

Estrogen and progesterone have been extensively studied in the mammary gland, but the molecular effects of androgen remain largely unexplored. Transgender men are recorded as female at birth but identify as male and may undergo gender-affirming androgen therapy to align their physical characteristics and gender identity. Here we perform single-cell-resolution transcriptome, chromatin, and spatial profiling of breast tissues from transgender men following androgen therapy. We find canonical androgen receptor gene targets are upregulated in cells expressing the androgen receptor and that paracrine signaling likely drives sex-relevant androgenic effects in other cell types. We also observe involution of the epithelium and a spatial reconfiguration of immune, fibroblast, and vascular cells, and identify a gene regulatory network associated with androgen-induced fat loss. This work elucidates the molecular consequences of androgen activity in the human breast at single-cell resolution.
A unifying statistical framework to discover disease genes from GWASs
Authors: Justin N.J. McManus, Robert J. Lovelett, Daniel Lowengrub, Sarah Christensen
Journal: Cell Genomics (2023)

Genome-wide association studies (GWASs) identify genomic loci associated with complex traits, but it remains a challenge to identify the genes affected by causal genetic variants in these loci. Attempts to solve this challenge are frustrated by a number of compounding problems. Here, we show how to combine solutions to these problems into a unified mathematical framework. From this synthesis, it becomes possible to compute the probability that each gene in the genome is affected by a causal variant, given a particular trait, without making assumptions about the relevant cell types or tissues. We validate each component of the framework individually and in combination. When applied to large GWASs of human disease, the resulting paradigm can rediscover the majority of well-known disease genes. Moreover, it establishes human genetics support for many genes previously implicated only by clinical or preclinical evidence, and it uncovers a plethora of novel disease genes with compelling biological rationale.
Mother-to-infant microbiota transmission and infant microbiota development across multiple body sites
Authors: Debby Bogaert, Gina J. van Beveren, Emma M. de Koff, Paula Lusarreta Parga, Carlos E. Balcazar Lopez, Lilian Koppensteiner, Melanie Clerc, Raiza Hasrat, Kayleigh Arp, Mei Ling J.N. Chu, Pieter C.M. de Groot, Elisabeth A.M. Sanders, Marlies A. van Houten, Wouter A.A. de Steenhuijsen Piters
Journal: Cell Host & Microbe (2023)
Glutamatergic and GABAergic neurons in pontine central gray mediate opposing valence-specific behaviors through a global network
Authors: Cuiyu Xiao, Jinxing Wei, Guang-wei Zhang, Can Tao, Junxiang J. Huang, Li Shen, Ian R. Wickersham, Huizhong W. Tao, Li I. Zhang
Journal: Neuron (2023)
Choroid plexus-targeted NKCC1 overexpression to treat post-hemorrhagic hydrocephalus
Authors: Cameron Sadegh, Huixin Xu, Jason Sutin, Benoit Fatou, Suhasini Gupta, Aja Pragana, Milo Taylor, Peter N. Kalugin, Miriam E. Zawadzki, Osama Alturkistani, Frederick B. Shipley, Neil Dani, Ryann M. Fame, Zainab Wurie, Pratik Talati, Riana L. Schleicher, Eric M. Klein, Yong Zhang, Michael J. Holtzman, Christopher I. Moore, Pei-Yi Lin, Aman B. Patel, Benjamin C. Warf, W. Taylor Kimberly, Hanno Steen, Mark L. Andermann, Maria K. Lehtinen
Journal: Neuron (2023)

Post-hemorrhagic hydrocephalus (PHH) refers to a life-threatening accumulation of cerebrospinal fluid (CSF) that occurs following intraventricular hemorrhage (IVH). An incomplete understanding of this variably progressive condition has hampered the development of new therapies beyond serial neurosurgical interventions. Here, we show a key role for the bidirectional Na-K-Cl cotransporter, NKCC1, in the choroid plexus (ChP) to mitigate PHH. Mimicking IVH with intraventricular blood led to increased CSF [K+] and triggered cytosolic calcium activity in ChP epithelial cells, which was followed by NKCC1 activation. ChP-targeted adeno-associated viral (AAV)-NKCC1 prevented blood-induced ventriculomegaly and led to persistently increased CSF clearance capacity. These data demonstrate that intraventricular blood triggered a trans-choroidal, NKCC1-dependent CSF clearance mechanism. Inactive, phosphodeficient AAV-NKCC1-NT51 failed to mitigate ventriculomegaly. Excessive CSF [K+] fluctuations correlated with permanent shunting outcome in humans following hemorrhagic stroke, suggesting targeted gene therapy as a potential treatment to mitigate intracranial fluid accumulation following hemorrhage.
Candida albicans-specific Th17 cell-mediated response contributes to alcohol-associated liver disease
Authors: Suling Zeng, Elisa Rosati, Carina Saggau, Berith Messner, Huikuan Chu, Yi Duan, Phillipp Hartmann, Yanhan Wang, Shengyun Ma, Wendy Jia Men Huang, Jihyung Lee, Sung Min Lee, Raquel Carvalho-Gontijo, Vivian Zhang, Joseph P. Hoffmann, Jay K. Kolls, Eyal Raz, David A. Brenner, Tatiana Kisseleva, Salomé LeibundGut-Landmann, Petra Bacher, Peter Stärkel, Bernd Schnabl
Journal: Cell Host & Microbe (2023)
Efficacy and toxicity of adjuvant radiotherapy in recurrent melanoma after adjuvant immunotherapy
Authors: Prachi Bhave, Angela Hong, Serigne N Lo, Rebecca Johnson, Johanna Mangana, Douglas B Johnson, Ozgecan Dulgar, Zeynep Eroglu, Hui-Ling Yeoh, Andrew Haydon, Georg C Lodde, Elisabeth Livingstone, Adnan Khattak, Katharina Kähler, Axel Hausschild, Grant A McArthur, Alexander Maxwell Menzies, Georgina Long, Wei Wang, Matteo S Carlino
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background In patients with stage III melanoma, despite surgical resection and adjuvant systemic therapy, locoregional recurrences still occur. The randomized, phase III Trans-Tasman Radiation Oncology Group (TROG) 02.01 trial demonstrated that adjuvant radiotherapy (RT) after complete lymphadenectomy (CLND) halves the incidence of melanoma recurrence within local nodal basins without improving overall survival or quality of life. However, the study was conducted prior to the current era of adjuvant systemic therapies and when CLND was the standard approach for microscopic nodal disease. As such, there is currently no data on the role of adjuvant RT in patients with melanoma who recur during or after adjuvant immunotherapy, including those that may or may not have undergone prior CLND. In this study, we aimed to answer this question. Methods Patients with resected stage III melanoma who received adjuvant anti-programmed cell death protein-1 (PD-1) (±ipilimumab) immunotherapy with a subsequent locoregional (lymph node and/or in-transit metastases) recurrence were retrospectively identified. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was rate of subsequent locoregional recurrence; secondary outcomes were locoregional recurrence-free survival (lr-RFS2) and overall RFS (RFS2) to second recurrence. Results In total, 71 patients were identified: 42 (59%) men, 30 (42%) BRAF V600E mutant, 43 (61%) stage IIIC at diagnosis. Median time to first recurrence was 7 months (1–44), 24 (34%) received adjuvant RT and 47 (66%) did not. Thirty-three patients (46%) developed a second recurrence at a median of 5 months (1–22). The rate of locoregional relapse at second recurrence was lower in those who received adjuvant RT (8%, 2/24) compared with those who did not (36%, 17/47, p=0.01). Adjuvant RT at first recurrence was associated with an improved lr-RFS2 (HR 0.16, p=0.015), with a trend towards an improved RFS2 (HR 0.54, p = 0.072) and no effect on risk of distant recurrence or overall survival. Conclusion This is the first study to investigate the role of adjuvant RT in patients with melanoma with locoregional disease recurrence during or after adjuvant anti-PD-1-based immunotherapy. Adjuvant RT was associated with improved lr-RFS2, but not risk of distant recurrence, demonstrating a likely benefit in locoregional disease control in the modern era. Further prospective studies are required to validate these results.
Systemic inflammation shapes clinical outcomes in response to immune checkpoint blockade treatment: moving toward optimizing antitumor immunity
Authors: Ming Zheng
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Immune checkpoint blockade (ICB) treatment may induce durable disease remission, but only in a minority of patients with cancer. One important question is how to identify patients who may benefit from ICB treatment. ICB treatment relies on unleashing patients’ pre-existing immune responses. Focusing on the key components of immune response, this study proposes the neutrophil-to-lymphocyte ratio (NLR) as a simplified indicator of patients’ immune status to predict ICB treatment outcomes. Methods This study analyzed a large pan-cancer cohort of 16 cancer types, including 1714 patients with cancer who received ICB treatment. Clinical outcomes in response to ICB treatment were measured by overall survival (OS), progression-free survival (PFS), objective response rate, and clinical benefit rate. The non-linear relationships of NLR with OS and PFS were investigated by a spline-based multivariate Cox regression model. A total of 1000 randomly resampled cohorts were bootstrapped to estimate the variability and reproducibility of NLR-related ICB responses. Results By interrogating a clinically representative cohort, this study revealed a previously unreported finding that the pretreatment NLR levels were associated with ICB treatment outcomes in a U-shaped dose-dependent manner rather than a linear manner. An NLR range between 2.0 and 3.0 was remarkably associated with optimal ICB treatment outcomes, including increased patient survival, delayed disease progression, improved treatment response, and significant clinical benefit. Comparatively, either decreasing (&lt; 2.0) or increasing (&gt;3.0) NLR levels were indicators of worse ICB treatment outcomes. Furthermore, this study presents a comprehensive landscape of NLR-related ICB treatment outcomes across different patient populations defined by demographics, baseline characteristics, treatment, cancer-type-specific ICB responsiveness, and individual cancer type. Conclusions The NLR range from 2.0 to 3.0 might indicate an optimal balance between innate (neutrophils) and adaptive (lymphocytes) immune responses that potentiates antitumor immunity, which was observed in only 18.6% of patients. A majority of patients showed decreasing NLR (&lt;2.00; 10.9% patients) or increasing NLR (&gt;3.00; 70.5% patients), representing two distinct types of immune dysregulation associated with ICB resistance. This study translates routine blood tests into a precision medicine-based approach to immunotherapy, with important implications for clinicians in clinical decision-making as well as for regulatory agencies in drug approvals.
Scarlett McNally: International Women’s Day—and how institutions and individuals can reduce sexism in healthcare
Authors: Scarlett McNally
Journal: BMJ (2023)

On International Women's Day, let's pause and consider whether there's a link between the burden that a medical career places on women and the imminent strikes by doctors in training.Does the traditional medical training model expect too much relentless, self-sacrificial overwork?Does it rely on undervalued back-up from a supportive partner to help sort out childcare and home administration?Women have outnumbered men at medical school in the UK for 30 years. 1 Yet a recent BMA survey found that 91% of female doctors had experienced sexism at work since 2019. 2 We must do better for the next generation of women in medicine.
A multicenter retrospective study of calcineurin inhibitors in nephrotic syndrome secondary to podocyte gene variants
Authors: Georgia Malakasioti, Daniela Iancu, Anastasiia Milovanova, Alexey Tsygin, Tomoko Horinouchi, China Nagano, Kandai Nozu, Koichi Kamei, Shuichiro Fujinaga, Kazumoto Iijima, Hee Gyung Kang, Rajiv Sinha, Biswanath Basu, William Morello, Giovanni Montini, Aoife Waters, Olivia Boyer, Zeynep Yürük Yıldırım, Sibel Yel, İsmail Dursun, Hugh J. McCarthy, Marina Vivarelli, Larisa Prikhodina, Martine T.P. Besouw, Eugene Yu-hin Chan, Wenyan Huang, Markus J. Kemper, Sebastian Loos, Chanel Prestidge, William Wong, Galia Zlatanova, Rasmus Ehren, Lutz T. Weber, Hassib Chehade, Nakysa Hooman, Marcin Tkaczyk, Małgorzata Stańczyk, Michael Miligkos, Kjell Tullus
Journal: Kidney International (2023)
The fatty acid elongase Elovl6 is crucial for hematopoietic stem cell engraftment and leukemia propagation
Authors: Yusuke Kiyoki, Takayasu Kato, Sakura Kito, Takashi Matsuzaka, Shin Morioka, Junko Sasaki, Kenichi Makishima, Tatsuhiro Sakamoto, Hidekazu Nishikii, Naoshi Obara, Mamiko Sakata-Yanagimoto, Takehiko Sasaki, Hitoshi Shimano, Shigeru Chiba
Journal: Leukemia (2023)
Immune cell membrane-based biomimetic nanomedicine for treating cancer metastasis
Authors: Lingling Zhu, Xianzhe Yu, Ting Cao, Hanyu Deng, Xiaojun Tang, Qing Lin, Qinghua Zhou
Journal: Acta Pharmaceutica Sinica B (2023)

Metastasis is the leading cause of cancer-related death. Despite extensive treatment, the prognosis for patients with metastatic cancer remains poor. In addition to conventional surgical resection, radiotherapy, immunotherapy, chemotherapy, and targeted therapy, various nanobiomaterials have attracted attention for their enhanced antitumor performance and low off-target effects. However, nanomedicines exhibit certain limitations in clinical applications, such as rapid clearance from the body, low biological stability, and poor targeting ability. Biomimetic methods utilize the natural biomembrane to mimic or hybridize nanoparticles and circumvent some of these limitations. Considering the involvement of immune cells in the tumor microenvironment of the metastatic cascade, biomimetic methods using immune cell membranes have been proposed with unique tumor-homing ability and high biocompatibility. In this review, we explore the impact of immune cells on various processes of tumor metastasis. Furthermore, we summarize the synthesis and applications of immune cell membrane-based nanocarriers increasing therapeutic efficacy against cancer metastases via immune evasion, prolonged circulation, enhanced tumor accumulation, and immunosuppression of the tumor microenvironment. Moreover, we describe the prospects and existing challenges in clinical translation.
Upadacitinib Is Effective and Safe in Both Ulcerative Colitis and Crohn’s Disease: Prospective Real-World Experience
Authors: Scott Friedberg, David Choi, Thomas Hunold, Natalie K. Choi, Nicole M. Garcia, Emma A. Picker, Nathaniel A. Cohen, Russell D. Cohen, Sushila R. Dalal, Joel Pekow, Atsushi Sakuraba, Noa Krugliak Cleveland, David T. Rubin
Journal: Clinical Gastroenterology and Hepatology (2023)
Ambient air pollution exposure linked to long COVID among young adults: a nested survey in a population-based cohort in Sweden
Authors: Zhebin Yu, Sandra Ekström, Tom Bellander, Petter Ljungman, Göran Pershagen, Kristina Eneroth, Inger Kull, Anna Bergström, Antonios Georgelis, Massimo Stafoggia, Olena Gruzieva, Erik Melén, Catarina Almqvist, Niklas Andersson, Natalia Ballardini, Anna Bergström, Sophia Björkander, Petter Brodin, Anna Castel, Sandra Ekström, Antonios Georgelis, Lennart Hammarström, Qiang Pan-Hammarström, Jenny Hallberg, Christer Jansson, Maura Kere, Inger Kull, André Lauber, Alexandra Lövquist, Erik Melén, Jenny Mjösberg, Ida Mogensen, Lena Palmberg, Göran Pershagen, Niclas Roxhed, Jochen Schwenk
Journal: The Lancet Regional Health - Europe (2023)

Post COVID-19 conditions, also known as long COVID, are of public health concern, but little is known about their underlying risk factors. We aimed to investigate associations of air pollution exposure with long COVID among Swedish young adults.We used data from the BAMSE (Children, Allergy, Environment, Stockholm, Epidemiology [in Swedish]) cohort. From October 2021 to February 2022 participants answered a web-questionnaire focusing on persistent symptoms following acute SARS-CoV-2 infection. Long COVID was defined as symptoms after confirmed infection with SARS-CoV-2 lasting for two months or longer. Ambient air pollution levels (particulate matter ≤2.5 μm [PM2.5], ≤10 μm [PM10], black carbon [BC] and nitrogen oxides [NOx]) at individual-level addresses were estimated using dispersion modelling.A total of 753 participants with SARS-CoV-2 infection were included of whom 116 (15.4%) reported having long COVID. The most common symptoms were altered smell/taste (n = 80, 10.6%), dyspnea (n = 36, 4.8%) and fatigue (n = 34, 4.5%). Median annual PM2.5 exposure in 2019 (pre-pandemic) was 6.39 (interquartile range [IQR] 6.06-6.71) μg/m3. Adjusted Odds Ratios (95% confidence intervals) of PM2.5 per IQR increase were 1.28 (1.02-1.60) for long COVID, 1.65 (1.09-2.50) for dyspnea symptoms and 1.29 (0.97-1.70) for altered smell/taste. Positive associations were found for the other air pollutants and remained consistent across sensitivity analyses. Associations tended to be stronger among participants with asthma, and those having had COVID during 2020 (versus 2021).Ambient long-term PM2.5 exposure may affect the risk of long COVID in young adults, supporting efforts for continuously improving air quality.The study received funding from the Swedish Research Council (grant no. 2020-01886, 2022-06340), the Swedish Research Council for Health, Working life and Welfare (FORTE grant no. 2017-01146), the Swedish Heart-Lung Foundation, Karolinska Institute (no. 2022-01807) and Region Stockholm (ALF project for cohort and database maintenance).
Dual stimulus responsive borosilicate glass (BSG) scaffolds promote diabetic alveolar bone defectsrepair by modulating macrophage phenotype
Authors: Pengfei Tian, Limin Zhao, Jua Kim, Xian Li, Chunyu Liu, Xu Cui, Tao Liang, Yunbo Du, Xiehui Chen, Haobo Pan
Journal: Bioactive Materials (2023)

The regeneration of alveolar bone is still clinical challenge, particularly accompanied with diabetes, causing metabolic disorder with a protracted low-grade inflammatory phenotype. As a result, the anticipated loading of biomaterials is highly suspicious in spontaneous modulation of cells function, which is mostly disturbed by constant inflammation. In this study, we developed glucose and hydrogen peroxide dual-responsive borosilicate glass (BSG) scaffolds loaded with epigallocatechin gallate (EGCG) to synergistically modulate the abnormal inflammation of diabetic alveolar bone defects. It was found that the release of EGCG by BSG could directly regulate the shift of macrophages from M1 to the M2 phenotype by promoting autophagy and lessening the inhibition of autophagic flux. Moreover, EGCG can also indirectly regulate the polarization phenotype of macrophages by reducing the activation of NF-κb in stem cells and restoring its immunoregulatory capacity. Therefore, the addition of EGCG to BSG scaffold in diabetes allows for a more striking modulation of the macrophage phenotype in a timely manner. The altered macrophage phenotype reduces local inflammation and thus increases the ability to repair diabetic alveolar bone, showing promise for the treatment of alveolar defect in diabetic patients.